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This article is from PLoS ONE , volume 9 . Abstract Background: The relationship between uncoupling protein (UCP) 1–3 polymorphisms and susceptibility to obesity has been investigated in several genetic studies. However, the impact of these polymorphisms on obesity is still under debate, with contradictory results being reported. Until this date, no meta-analysis evaluated the association of UCP polymorphisms with body mass index (BMI) variability. Thus, this paper describe a meta-analysis conducted to evaluate if the -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3) polymorphisms are associated with BMI changes. Methods: A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and BMI. Weighted mean differences (WMD) were calculated for different inheritance models. Results: Fifty-six studies were eligible for inclusion in the meta-analysis. Meta-analysis results showed that UCP2 55Val/Val genotype was associated with increased BMI in Europeans [Random Effect Model (REM) WMD 0.81, 95% CI 0.20, 1.41]. Moreover, the UCP2 Ins allele and UCP3-55T/T genotype were associated with increased BMI in Asians [REM WMD 0.46, 95% CI 0.09, 0.83 and Fixed Effect Model (FEM) WMD 1.63, 95% CI 0.25, 3.01]. However, a decreased BMI mean was observed for the UCP2-866 A allele in Europeans under a dominant model of inheritance (REM WMD −0.18, 95% CI −0.35, −0.01). There was no significant association of the UCP1-3826A/G polymorphism with BMI mean differences. Conclusions: The meta-analysis detected a significant association between the UCP2-866G/A, Ins/Del, Ala55Val and UCP3-55C/T polymorphisms and BMI mean differences.

This article is from PLoS ONE , volume 9 . Abstract Background: The relationship between uncoupling protein (UCP) 1–3 polymorphisms and susceptibility to obesity has been investigated in several genetic studies. However, the impact of these polymorphisms on obesity is still under debate, with contradictory results being reported. Until this date, no meta-analysis evaluated the association of UCP polymorphisms with body mass index (BMI) variability. Thus, this paper describe a meta-analysis conducted to evaluate if the -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3) polymorphisms are associated with BMI changes. Methods: A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and BMI. Weighted mean differences (WMD) were calculated for different inheritance models. Results: Fifty-six studies were eligible for inclusion in the meta-analysis. Meta-analysis results showed that UCP2 55Val/Val genotype was associated with increased BMI in Europeans [Random Effect Model (REM) WMD 0.81, 95% CI 0.20, 1.41]. Moreover, the UCP2 Ins allele and UCP3-55T/T genotype were associated with increased BMI in Asians [REM WMD 0.46, 95% CI 0.09, 0.83 and Fixed Effect Model (FEM) WMD 1.63, 95% CI 0.25, 3.01]. However, a decreased BMI mean was observed for the UCP2-866 A allele in Europeans under a dominant model of inheritance (REM WMD −0.18, 95% CI −0.35, −0.01). There was no significant association of the UCP1-3826A/G polymorphism with BMI mean differences. Conclusions: The meta-analysis detected a significant association between the UCP2-866G/A, Ins/Del, Ala55Val and UCP3-55C/T polymorphisms and BMI mean differences.

This article is from PLoS ONE , volume 9 . Abstract Background: The relationship between uncoupling protein (UCP) 1–3 polymorphisms and susceptibility to obesity has been investigated in several genetic studies. However, the impact of these polymorphisms on obesity is still under debate, with contradictory results being reported. Until this date, no meta-analysis evaluated the association of UCP polymorphisms with body mass index (BMI) variability. Thus, this paper describe a meta-analysis conducted to evaluate if the -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3) polymorphisms are associated with BMI changes. Methods: A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and BMI. Weighted mean differences (WMD) were calculated for different inheritance models. Results: Fifty-six studies were eligible for inclusion in the meta-analysis. Meta-analysis results showed that UCP2 55Val/Val genotype was associated with increased BMI in Europeans [Random Effect Model (REM) WMD 0.81, 95% CI 0.20, 1.41]. Moreover, the UCP2 Ins allele and UCP3-55T/T genotype were associated with increased BMI in Asians [REM WMD 0.46, 95% CI 0.09, 0.83 and Fixed Effect Model (FEM) WMD 1.63, 95% CI 0.25, 3.01]. However, a decreased BMI mean was observed for the UCP2-866 A allele in Europeans under a dominant model of inheritance (REM WMD −0.18, 95% CI −0.35, −0.01). There was no significant association of the UCP1-3826A/G polymorphism with BMI mean differences. Conclusions: The meta-analysis detected a significant association between the UCP2-866G/A, Ins/Del, Ala55Val and UCP3-55C/T polymorphisms and BMI mean differences.

This article is from BMC Cardiovascular Disorders , volume 14 . Abstract Background: We investigated the effects of uncoupling protein 3 (UCP3) genetic deletion on 18F-fluorodeoxyglucose (FDG) cardiac uptake by positron emission tomography (PET)/computed tomography (CT) dedicated animal system after permanent coronary artery ligation. Methods: Cardiac 18F-FDG PET/CT was performed in UCP3 knockout (UCP3−/−) and wild-type (WT) mice one week after induction of myocardial infarction or sham procedure. Results: In sham-operated mice no difference in left ventricular (LV) volume was detectable between WT and UCP3−/−. After myocardial infarction, LV volume was higher in both WT and UCP3−/− compared to sham animals, with a significant interaction (p 

This article is from BMC Cardiovascular Disorders , volume 14 . Abstract Background: We investigated the effects of uncoupling protein 3 (UCP3) genetic deletion on 18F-fluorodeoxyglucose (FDG) cardiac uptake by positron emission tomography (PET)/computed tomography (CT) dedicated animal system after permanent coronary artery ligation. Methods: Cardiac 18F-FDG PET/CT was performed in UCP3 knockout (UCP3−/−) and wild-type (WT) mice one week after induction of myocardial infarction or sham procedure. Results: In sham-operated mice no difference in left ventricular (LV) volume was detectable between WT and UCP3−/−. After myocardial infarction, LV volume was higher in both WT and UCP3−/− compared to sham animals, with a significant interaction (p 

This article is from PLoS ONE , volume 9 . Abstract In the 4-cell C. elegans embryo, a signal from P2 to its anterior sister, EMS, specifies the posterior daughter of EMS, E, as the sole founder cell for intestine. The P2-to-EMS signal restricts high level zygotic expression of the redundant GATA transcription factors, END-1 and END-3, to only the E lineage. Expression of END-1 or END-3 in early blastomeres is sufficient to drive intestinal differentiation. We show here that a number of E lineage characteristics, which are also regulated through P2-EMS signaling, can be uncoupled from intestine development, and each with a different sensitivity to specific perturbations of the P2-EMS signal. For example, we show that the extended cell cycle in Ea and Ep depends on the P2-induced high level expression of the cell cycle regulator, WEE-1.1, in E. A mutation in wee-1.1 results in shortened Ea and Ep cell cycles, but has no effect upon intestinal differentiation or embryogenesis. Furthermore, it has been shown previously that the total number of E lineage cell divisions is regulated by a mechanism dependent upon E being specified as the intestinal founder cell. We now show, however, that cell division counting can be uncoupled from intestine differentiation in the E lineage. Many mutations in P2-EMS signal genes exhibit nonfully-penetrant defects in intestinal differentiation. When embryos with those mutations generate intestinal cells, they often make too many intestinal cells. In addition, at the level of individual embryos, expression of end-1 and end-3, and another very early E-specific zygotic gene, sdz-23, exhibit stochastic and discordant defects in P2-EMS signaling mutants. We show here that sdz-23 is expressed close to wildtype levels in embryos deleted of both end-1 and end-3. sdz-23 does not appear to function in intestine development, raising the intriguing possibility that the P2-EMS interaction has downstream molecular consequences within the E lineage independent of end-1/3 and intestinal development.

This article is from Frontiers in Physiology , volume 5 . Abstract Contraction in the mammalian heart is controlled by the intracellular Ca2+ concentration as it is in all striated muscle, but the heart has an additional signaling system that comes into play to increase heart rate and cardiac output during exercise or stress. β-adrenergic stimulation of heart muscle cells leads to release of cyclic-AMP and the activation of protein kinase A which phosphorylates key proteins in the sarcolemma, sarcoplasmic reticulum and contractile apparatus. Troponin I (TnI) and Myosin Binding Protein C (MyBP-C) are the prime targets in the myofilaments. TnI phosphorylation lowers myofibrillar Ca2+-sensitivity and increases the speed of Ca2+-dissociation and relaxation (lusitropic effect). Recent studies have shown that this relationship between Ca2+-sensitivity and TnI phosphorylation may be unstable. In familial cardiomyopathies, both dilated and hypertrophic (DCM and HCM), a mutation in one of the proteins of the thin filament often results in the loss of the relationship (uncoupling) and blunting of the lusitropic response. For familial dilated cardiomyopathy in thin filament proteins it has been proposed that this uncoupling is causative of the phenotype. Uncoupling has also been found in human heart tissue from patients with hypertrophic obstructive cardiomyopathy as a secondary effect. Recently, it has been found that Ca2+-sensitizing drugs can promote uncoupling, whilst one Ca2+-desensitizing drug Epigallocatechin 3-Gallate (EGCG) can reverse uncoupling. We will discuss recent findings about the role of uncoupling in the development of cardiomyopathies and the molecular mechanism of the process.

Specifically, the work will focus on conducting an in-depth review of literature demonstrating that the uncoupling proteins inhibit mitochondrial reactive oxygen species (ROS) production by inducing what is referred to as “proton leaks”, which refers to the passive return of protons to the mitochondrial matrix, by-passing ATP synthase. The importance of this work stems from twenty years of empirical evidence demonstrating that the uncoupling proteins function in this capacity. However, despite this, the function of uncoupling proteins in suppressing mitochondrial ROS production is not universally accepted. Therefore, the goal of this systematic review is to provide a clear demonstration that the uncoupling proteins function in this manner, which will be achieved via the in-depth review of the literature.

Specifically, the work will focus on conducting an in-depth review of literature demonstrating that the uncoupling proteins inhibit mitochondrial reactive oxygen species (ROS) production by inducing what is referred to as “proton leaks”, which refers to the passive return of protons to the mitochondrial matrix, by-passing ATP synthase. The importance of this work stems from twenty years of empirical evidence demonstrating that the uncoupling proteins function in this capacity. However, despite this, the function of uncoupling proteins in suppressing mitochondrial ROS production is not universally accepted. Therefore, the goal of this systematic review is to provide a clear demonstration that the uncoupling proteins function in this manner, which will be achieved via the in-depth review of the literature.

This article is from Journal of Virology , volume 87 . Abstract Transcription and replication of the influenza A virus RNA genome are mediated by the viral RNA polymerase from a promoter consisting of the partially base-paired 3′ and 5′ termini of viral genome segments. Here we show that transcription and replication can be uncoupled by mutation of an unpaired adenosine in the 5′ strand of the promoter. This residue is important for transcription but not replication by being essential for the cap-binding activity of the RNA polymerase.

Navigating Intimate Relationships, Uncoupling and More in The Journey Of Awakening | The Great Awakening with Bobby Balboa Hey friends! Welcome back to the show and to another great conscious conversation with Bobby Balboa and I. Today, we share our hearts and minds with you on what the journey of awakening brings when we are growing ourselves and expanding our consciousness. For many relationships, this brings a lot of challenge, as usually each individual in a relationship is awakening at a different time and in their own unique, and divine, way. We explore all aspects of this, as this situation has been very true for each of us. I share my lessons from becoming divorced in 2016, navigating challenges of remarrying abroad, and all the wisdom that my heart has shared with me through a lot of years of relationship challenges ( and 12 years of being married!). Bobby shares wisdom and important reflection at his current stage of awakening and allowing his relationship to shift during these days as well.  There is so much goodness in this episode for all of us awakening - and especially those of us who are in a relationship crossroads or maybe have been in recent years. With everything shifting so quickly, it is easy to feel like you are outgrowing your partner or needing a change and shift. PLEASE listen to this episode if you find yourself in this situation. With tremendous LOVE, Ivy You can find Bobby online: Instagram: @bobby_90july_ Youtube: https://www.youtube.com/results?search_query=bobby+balboa+tv Lorie Ladd: https://www.youtube.com/channel/UCXxn1HpP2HYaRjgqf1MXx0A Find me online at: [email protected] Instagram: @ivys.podcast , @healwithivy and @sovereign.ivy_ Parler: @sovereignivy Twitter: @sovereignivy YouTube: https://www.youtube.com/channel/UCXvIp7OZ-nYq0MKQe9YRvSQ/ -------------------------------------- Disclaimer: This podcast and the words, conversations, guests, and resources here are intended for your support, encouragement, inspiration and re-education. Nothing here is ever intended to diagnose, prescribe, treat or cure. Our health is our own responsibility, and you are empowered to exercise wise discernment, educate yourself, ask amazing questions, and always seek accurate information and practice informed consent. Always seek a medical professional that you trust when when you need to. --- This episode is sponsored by - Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/sovereignsoulradio/support

In this episode of the Making Sense podcast, Sam Harris speaks with Andrew McAfee about the history of human progress and the modern uncoupling of our prosperity from resource consumption. They discuss the pitfalls and hidden virtues of capitalism, technological progress, environmental policy, the future of the developing world, and other topics. SUBSCRIBE to listen to the rest of this episode and gain access to all full-length episodes of the podcast at samharris.org/subscribe.

This article is from Oncotarget , volume 5 . Abstract The p53-Mdm2 feedback loop is thought to be the main mechanism by which p53 autoregulates its levels and activity after DNA damage. We tested this paradigm in a genetically engineered mouse model in which the feedback loop was disrupted by point mutations in the p53 binding site of the Mdm2 promoter. We noted that while the p53-Mdm2 feedback loop is required to regulate p53 activity especially in the hematopoietic system in response to DNA damage, its role in development and in regulating the stability of p53 is dispensable. In the present study we have extended our characterization of this mouse model and show that the kinetics of p53 degradation is also unchanged in mouse embryonic fibroblasts (MEFs). Additionally, MG132 experiments indicate that other E3-ligases regulate p53 stability. Also, Mdm4 cooperates in inhibition of p53 activity and levels in these mice. Finally, we show in this system that enhanced acute p53 response does not promote aging or protect against late term tumorigenesis. We also discuss future perspectives for this study.

This article is from Oncotarget , volume 5 . Abstract The p53-Mdm2 feedback loop is thought to be the main mechanism by which p53 autoregulates its levels and activity after DNA damage. We tested this paradigm in a genetically engineered mouse model in which the feedback loop was disrupted by point mutations in the p53 binding site of the Mdm2 promoter. We noted that while the p53-Mdm2 feedback loop is required to regulate p53 activity especially in the hematopoietic system in response to DNA damage, its role in development and in regulating the stability of p53 is dispensable. In the present study we have extended our characterization of this mouse model and show that the kinetics of p53 degradation is also unchanged in mouse embryonic fibroblasts (MEFs). Additionally, MG132 experiments indicate that other E3-ligases regulate p53 stability. Also, Mdm4 cooperates in inhibition of p53 activity and levels in these mice. Finally, we show in this system that enhanced acute p53 response does not promote aging or protect against late term tumorigenesis. We also discuss future perspectives for this study.

Join me as I dive into the transformative practice of Conscious Uncoupling with my guest Greg Wheeler, a certified coach in this revolutionary approach. Discover how Conscious Uncoupling, based on Katherine Woodward Thomas's principles, helps individuals navigate divorce with empathy and respect, even in high-conflict situations. Greg shares insights on healing, co-parenting, and creating a positive future post-divorce. Whether you're facing a narcissistic divorce or seeking a better way to part ways, this discussion offers practical advice and hope. Greg Wheeler is a certified Conscious Uncoupling coach and author, dedicated to helping individuals and couples navigate divorce with compassion and clarity. With a background in engineering and a personal journey through divorce, Greg brings a unique perspective on healing and rebuilding after relationship breakdowns. Visit Greg's website: www.GregWheelerCoaching.com

Join me as I dive into the transformative practice of Conscious Uncoupling with my guest Greg Wheeler, a certified coach in this revolutionary approach. Discover how Conscious Uncoupling, based on Katherine Woodward Thomas's principles, helps individuals navigate divorce with empathy and respect, even in high-conflict situations. Greg shares insights on healing, co-parenting, and creating a positive future post-divorce. Whether you're facing a narcissistic divorce or seeking a better way to part ways, this discussion offers practical advice and hope. Greg Wheeler is a certified Conscious Uncoupling coach and author, dedicated to helping individuals and couples navigate divorce with compassion and clarity. With a background in engineering and a personal journey through divorce, Greg brings a unique perspective on healing and rebuilding after relationship breakdowns. Visit Greg's website: www.GregWheelerCoaching.com

Join me as I dive into the transformative practice of Conscious Uncoupling with my guest Greg Wheeler, a certified coach in this revolutionary approach. Discover how Conscious Uncoupling, based on Katherine Woodward Thomas's principles, helps individuals navigate divorce with empathy and respect, even in high-conflict situations. Greg shares insights on healing, co-parenting, and creating a positive future post-divorce. Whether you're facing a narcissistic divorce or seeking a better way to part ways, this discussion offers practical advice and hope. Greg Wheeler is a certified Conscious Uncoupling coach and author, dedicated to helping individuals and couples navigate divorce with compassion and clarity. With a background in engineering and a personal journey through divorce, Greg brings a unique perspective on healing and rebuilding after relationship breakdowns. Visit Greg's website: www.GregWheelerCoaching.com

Join me as I dive into the transformative practice of Conscious Uncoupling with my guest Greg Wheeler, a certified coach in this revolutionary approach. Discover how Conscious Uncoupling, based on Katherine Woodward Thomas's principles, helps individuals navigate divorce with empathy and respect, even in high-conflict situations. Greg shares insights on healing, co-parenting, and creating a positive future post-divorce. Whether you're facing a narcissistic divorce or seeking a better way to part ways, this discussion offers practical advice and hope. Greg Wheeler is a certified Conscious Uncoupling coach and author, dedicated to helping individuals and couples navigate divorce with compassion and clarity. With a background in engineering and a personal journey through divorce, Greg brings a unique perspective on healing and rebuilding after relationship breakdowns. Visit Greg's website: www.GregWheelerCoaching.com

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This article is from Toxins , volume 2 . Abstract Staphylococcus aureus enterotoxins have immunomodulatory properties. In this study, we show that Staphylococcal enterotoxin A (SEA) induces a strong proliferative response in a murine T cell clone independent of MHC class II bearing cells. SEA stimulation also induces a state of hypo-responsiveness (anergy). We characterized the components of the T cell receptor (TCR) during induction of anergy by SEA. Most interestingly, TCR zeta chain phosphorylation was absent under SEA anergizing conditions, which suggests an uncoupling of zeta chain function. We characterize here a model system for studying anergy in the absence of confounding costimulatory signals.

This article is from Toxins , volume 2 . Abstract Staphylococcus aureus enterotoxins have immunomodulatory properties. In this study, we show that Staphylococcal enterotoxin A (SEA) induces a strong proliferative response in a murine T cell clone independent of MHC class II bearing cells. SEA stimulation also induces a state of hypo-responsiveness (anergy). We characterized the components of the T cell receptor (TCR) during induction of anergy by SEA. Most interestingly, TCR zeta chain phosphorylation was absent under SEA anergizing conditions, which suggests an uncoupling of zeta chain function. We characterize here a model system for studying anergy in the absence of confounding costimulatory signals.

This article is from Cellular Signalling , volume 26 . Abstract Angiopoietin-1 (Ang1) is a ligand for the receptor tyrosine kinase Tie2 and has key roles in the development of the vascular system and vascular protection. In a screen to define signalling pathways regulated by Ang1 in endothelial cells we found the RNA-binding protein hnRNP-K to be phosphorylated in response to Ang1. The ligand stimulated both tyrosine phosphorylation of hnRNP-K and recruitment of the tyrosine kinase Src to the RNA-binding protein. In endothelial cells hnRNP-K was found bound to mRNA encoding the mitochondrial protein uncoupling protein-2 (UCP2). Ang1 stimulation of cells resulted in the release of UCP2 mRNA from hnRNP-K. Using in vitro assays we confirmed direct binding between hnRNP-K and UCP2 mRNA. Furthermore Src induced phosphorylation of purified hnRNP-K and prevented UCP2 mRNA binding. Tyrosine 458 in the RNA-binding protein was found to be required for suppression of UCP2 mRNA binding by Src phosphorylation. In addition to releasing UCP2 mRNA from hnRNP-K, Ang1 induced an increase in UCP2 protein expression in endothelial cells without affecting total UCP2 mRNA levels. Consistent with the known effects of UCP2 to suppress generation of reactive oxygen species, Ang1 limited ROS production in endothelium stimulated with tumour necrosis factor-α. Taken together these data suggest that UCP2 mRNA is present in endothelial cells bound to hnRNP-K, which holds it in a translationally inactive state, and that Ang1 stimulates Src interaction with hnRNP-K, phosphorylation of the RNA-binding protein, release of these transcripts and upregulation of UCP2 protein expression. This study demonstrates a new mechanism for post-transcriptional regulation of UCP2 by the vascular protective ligand Ang1. The ability to rapidly upregulate UCP2 protein expression may be important in protecting endothelial cells from excessive generation of potentially damaging reactive oxygen species.

This article is from Frontiers in Oncology , volume 4 . Abstract None

Bacillus anthracis lethal toxin (LT) was characterized in plasma from infected African Green monkeys, rabbits, and guinea pigs. In all cases, during the terminal phase of infection only the protease-activated 63-kDa form of protective antigen (PA63) and the residual 20-kDa fragment (PA20) were detected in the plasma. No uncut PA with a molecular mass of 83 kDa was detected in plasma from toxemic animals during the terminal stage of infection. PA63 was largely associated with lethal factor (LF), forming LT. Characterization of LT by Western blotting, capture enzyme-linked immunosorbent assay, and size exclusion chromatography revealed that the antiphagocytic poly- -D-glutamic acid ( -DPGA) capsule released from B. anthracis bacilli was associated with LT in animal blood in variable amounts. While the nature of this in vivo association is not understood, we were able to determine that a portion of these LT/ -DPGA complexes retained LF protease activity. Our findings suggest that the in vivo LT complexes differ from in vitro-produced LT and that including -DPGA when examining the effects of LT on specific immune cells in vitro may reveal novel and important roles for -DPGA in anthrax pathogenesis.

This article is from Nature Communications , volume 3 . Abstract Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain. Fragile X mental retardation protein deletion in mice enhances metabotropic glutamate receptor-5-dependent long-term depression in the hippocampus and cerebellum. Here we show that a distinct type of metabotropic glutamate receptor-5-dependent long-term depression at excitatory synapses of the ventral striatum and prefrontal cortex, which is mediated by the endocannabinoid 2-arachidonoyl-sn-glycerol, is absent in fragile X mental retardation protein-null mice. In these mutants, the macromolecular complex that links metabotropic glutamate receptor-5 to the 2-arachidonoyl-sn-glycerol-producing enzyme, diacylglycerol lipase-α (endocannabinoid signalosome), is disrupted and metabotropic glutamate receptor-5-dependent 2-arachidonoyl-sn-glycerol formation is compromised. These changes are accompanied by impaired endocannabinoid-dependent long-term depression. Pharmacological enhancement of 2-arachidonoyl-sn-glycerol signalling normalizes this synaptic defect and corrects behavioural abnormalities in fragile X mental retardation protein-deficient mice. The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.

This article is from Nature Communications , volume 3 . Abstract Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain. Fragile X mental retardation protein deletion in mice enhances metabotropic glutamate receptor-5-dependent long-term depression in the hippocampus and cerebellum. Here we show that a distinct type of metabotropic glutamate receptor-5-dependent long-term depression at excitatory synapses of the ventral striatum and prefrontal cortex, which is mediated by the endocannabinoid 2-arachidonoyl-sn-glycerol, is absent in fragile X mental retardation protein-null mice. In these mutants, the macromolecular complex that links metabotropic glutamate receptor-5 to the 2-arachidonoyl-sn-glycerol-producing enzyme, diacylglycerol lipase-α (endocannabinoid signalosome), is disrupted and metabotropic glutamate receptor-5-dependent 2-arachidonoyl-sn-glycerol formation is compromised. These changes are accompanied by impaired endocannabinoid-dependent long-term depression. Pharmacological enhancement of 2-arachidonoyl-sn-glycerol signalling normalizes this synaptic defect and corrects behavioural abnormalities in fragile X mental retardation protein-deficient mice. The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.

Join me as I dive into the transformative practice of Conscious Uncoupling with my guest Greg Wheeler, a certified coach in this revolutionary approach. Discover how Conscious Uncoupling, based on Katherine Woodward Thomas's principles, helps individuals navigate divorce with empathy and respect, even in high-conflict situations. Greg shares insights on healing, co-parenting, and creating a positive future post-divorce. Whether you're facing a narcissistic divorce or seeking a better way to part ways, this discussion offers practical advice and hope. Greg Wheeler is a certified Conscious Uncoupling coach and author, dedicated to helping individuals and couples navigate divorce with compassion and clarity. With a background in engineering and a personal journey through divorce, Greg brings a unique perspective on healing and rebuilding after relationship breakdowns. Visit Greg's website: www.GregWheelerCoaching.com

This article is from The Journal of Experimental Medicine , volume 210 . Abstract Synthetic retinoids activate RARA- or PML/RARA-dependent transcription, but fail to degrade RARA or PML/RARA protein, which is insufficient for eradication of acute promyelocytic leukemia.

This article is from Nucleic Acids Research , volume 42 . Abstract Antiviral defence in mammals is mediated through type-I interferons (IFNs). Viruses antagonise this process through expression of IFN antagonist proteins (IAPs). Understanding and modelling of viral escape mechanisms and the dynamics of IAP action has the potential to facilitate the development of specific and safe drugs. Here, we describe the dynamics of interference by selected viral IAPs, NS1 from Influenza A virus and NS3/4A from Hepatitis C virus. We used Tet-inducible IAP gene expression to uncouple this process from virus-driven dynamics. Stochastic activation of the IFN-β gene required the use of single-cell live imaging to define the efficacy of the inhibitors during the virus-induced signalling processes. We found significant correlation between the onset of IAP expression and halted IFN-β expression in cells where IFN-β induction had already occurred. These data indicate that IAPs not only prevent antiviral signalling prior to IFN-β induction, but can also stop the antiviral response even after it has been activated. We found reduced NF-κB activation to be the underlying mechanism by which activated IFN expression can be blocked. This work demonstrates a new mechanism by which viruses can antagonise the IFN response.

Background: Sera from convalescent Lassa fever patients often contains antibodies to Lassa virus (LASV) glycoprotein 1 (GP1), and glycoprotein 2 (GP2); Immunization of non-human primates with viral vectors expressing the arenaviral glycoprotein complex (GPC) confers full protective immunity against a lethal challenge with LASV. Thus, the development of native or quasi native recombinant LASV GP1 and GP2 as soluble, uncoupled proteins will improve current diagnostics, treatment, and prevention of Lassa fever. To this end, mammalian expression systems were engineered for production and purification of secreted forms of soluble LASV GP1 and GP2 proteins. Results: Determinants for mammalian cell expression of secreted uncoupled Lassa virus (LASV) glycoprotein 1 (GP1) and glycoprotein 2 (GP2) were established. Soluble GP1 was generated using either the native glycoprotein precursor (GPC) signal peptide (SP) or human IgG signal sequences (s.s.). GP2 was secreted from cells only when (1) the transmembrane (TM) domain was deleted, the intracellular domain (IC) was fused to the ectodomain, and the gene was co-expressed with a complete GP1 gene in cis; (2) the TM and IC domains were deleted and GP1 was co-expressed in cis; (3) expression of GP1 was driven by the native GPC SP. These data implicate GP1 as a chaperone for processing and shuttling GP2 to the cell surface. The soluble forms of GP1 and GP2 generated through these studies were secreted as homogeneously glycosylated proteins that contained high mannose glycans. Furthermore, observation of GP1 ectodomain shedding from cells expressing wild type LASV GPC represents a novel aspect of arenaviral glycoprotein expression. Conclusion: These results implicate GP1 as a chaperone for the correct processing and shuttling of GP2 to the cell surface, and suggest that native GPC SP plays a role in this process.

Background: Sera from convalescent Lassa fever patients often contains antibodies to Lassa virus (LASV) glycoprotein 1 (GP1), and glycoprotein 2 (GP2); Immunization of non-human primates with viral vectors expressing the arenaviral glycoprotein complex (GPC) confers full protective immunity against a lethal challenge with LASV. Thus, the development of native or quasi native recombinant LASV GP1 and GP2 as soluble, uncoupled proteins will improve current diagnostics, treatment, and prevention of Lassa fever. To this end, mammalian expression systems were engineered for production and purification of secreted forms of soluble LASV GP1 and GP2 proteins. Results: Determinants for mammalian cell expression of secreted uncoupled Lassa virus (LASV) glycoprotein 1 (GP1) and glycoprotein 2 (GP2) were established. Soluble GP1 was generated using either the native glycoprotein precursor (GPC) signal peptide (SP) or human IgG signal sequences (s.s.). GP2 was secreted from cells only when (1) the transmembrane (TM) domain was deleted, the intracellular domain (IC) was fused to the ectodomain, and the gene was co-expressed with a complete GP1 gene in cis; (2) the TM and IC domains were deleted and GP1 was co-expressed in cis; (3) expression of GP1 was driven by the native GPC SP. These data implicate GP1 as a chaperone for processing and shuttling GP2 to the cell surface. The soluble forms of GP1 and GP2 generated through these studies were secreted as homogeneously glycosylated proteins that contained high mannose glycans. Furthermore, observation of GP1 ectodomain shedding from cells expressing wild type LASV GPC represents a novel aspect of arenaviral glycoprotein expression. Conclusion: These results implicate GP1 as a chaperone for the correct processing and shuttling of GP2 to the cell surface, and suggest that native GPC SP plays a role in this process.

This article is from Plant Signaling & Behavior , volume 8 . Abstract In plants, the nitrate transporters, NRT1.1 and NRT2.1, are mainly responsible for nitrate uptake. Intriguingly, both nitrate transporters are located in a complementary manner in different cells layers of the mature root suggesting that their coordination should occur during nitrate uptake and plant growth. This hypothesis was examined on 5-d-old rape seedlings grown on agar medium supplemented with 1 or 5mM nitrate. Seedlings were treated with increasing potassium glutamate concentrations in order to uncouple the two nitrate transporters by inhibiting BnNRT2.1 expression and activity specifically. In both nitrate treatments, increasing the glutamate concentrations from 0.5 to 10mM induced a reduction in 15NO3- uptake and an inhibition of N assimilation. The decrease in 15NO3- uptake was caused by downregulation of BnNRT2.1 expression but surprisingly it was not compensated by the upregulation of BnNRT1.1. This created an unprecedented physiological situation where the effects of the nitrate signal on shoot growth were solely modulated by nitrate absorption. In these conditions, the osmotic water flow for volumetric shoot growth was mainly dependent on active nitrate transport and nitrate signaling. This behavior was confirmed by the allometric relationships found between changes in the root length with 15N and water accumulation in the shoot. These findings demonstrate that the BnNRT2.1 transporter is essential for nitrate uptake and growth, and renew the question of the respective roles of the NRT2.1 and NRT1.1 transporters in nitrate uptake and sensing at the whole plant level.

The main purpose of this study is to consider an uncoupling method for analyzing explosively loaded structures embedded in hysteretic media. The method, which is based on wave propagation considerations, can be viewed as the plane wave approximation extended to nonlinear problems. Free-field data (both traction and velocity vectors) must be known in order to apply the method. Accuracy of the approximation is shown to be quite good when applied to a series of one-dimensional soil-structure interaction problems, even when the structure and surrounding soil are both nonlinear. Multi-dimensional problems, and techniques for improving the method, are also discussed briefly.

This article is from Journal of Experimental Botany , volume 65 . Abstract We demonstrated that mitochondrial respiration contributes to energy balancing between nitrogen and carbon metabolism by competing for reductant with de novo NO3– assimilation and avoiding chloroplastic excess reductant.

A concerted effort has been made to analyze submerged structures under explosive loadings, by utilizing the Doubly Asymptotic Approximation (DAA), to account for the structure-fluid interaction. The current implementation of the DAA employs a modal analysis for the structure and a set of orthogonal functions (surface expansion functions) for the fluid, the latter being used to improve the conditioning of the governing response equations. The DAA yields exact results for high and low frequencies and produces a smooth transition between these limits. Since a more accurate fit at intermediate frequencies may prove to be important in some problems of interest, the DAA may prove to be inadequate in some cases. The Inertial-Damping Collocation Approximation (IDCA), gives exact results for low, high, and selected intermediate frequencies, and as such represents a potential improvement over the DAA.

Stability is proven for two second order, two step methods for uncoupling a system of two evolution equations with exactly skew symmetric coupling: the Crank-Nicolson Leap Frog (CNLF) combination and the BDF2-AB2 combination. The form of the coupling studied arises in spatial discretizations of the Stokes-Darcy problem. For CNLF we prove stability for the coupled system under the time step condition suggested by linear stability theory for the Leap-Frog scheme. This seems to be a first proof of a widely believed result. For BDF2-AB2 we prove stability under a condition that is better than the one suggested by linear stability theory for the individual methods. This report is an expended version of the one submitted for publication.